In order to defeat the Knight of Hell Abaddon and stop her from gaining control of Hell, hunter Dean Winchester agreed to bear the biblical Mark of Cain so he could power the First Blade and kill her. The Mark of Cain begins negatively effecting Dean, particularly after he wields the First Blade for the first time with Dean developing more and more of an urge to kill. Dean ultimately kills Abaddon in battle, but the effects of the Mark of Cain just grows worse. Finally, while facing Metatron in battle, Dean is killed but the Mark resurrects him as both a demon and a Knight of Hell. The now-demonic Dean departs with Crowley to "howl at the moon" and leaves Sam a note telling Sam to let him go. Sam is unaware of what truly happened to Dean and begins chasing him down with the help of Castiel.
On June 21, 2003, in Nyack, New York, Dean hunts Edward Trenton, a man who had become an unknown species of monster that eats livers. Dean tracks Edward back to his home and kills him, but was is by Edward's son Cole who believes that Dean murdered his father, not knowing that his father had become a monster. As a result, Cole swears revenge on Dean and spends the next fourteen years looking for him and a chance to kill him.
In an attempt to find Dean, Sam begins hunting for Crowley for answers with the help of Castiel. However, Castiel's stolen grace is now fading badly and while hunting demons for answers, something goes wrong as a result and Sam is injured, resulting in his right arm being left in a sling. Sam's attempts to summon or call Crowley fail and no demon will answer when he tries to summon them.
Two weeks after Dean's disappearance, a desperate Sam finds a man named Lester Morris at a bar who is drunk and wants revenge on his cheating wife. Seeing a chance to capture a demon, Sam tells Lester about crossroads deals and offers to help him summon a Crossroad Demon. Following Sam's instructions, Lester goes to a crossroads and performs a summoning ritual, bringing Dar to the crossroads where Sam has painted a devil's trap. Before Sam can reach Lester and stop him, he makes a deal with Dar for his wife to be killed. Sam takes Dar prisoner and strings her to a tree with Supernatural Handcuffs and begins torturing her for information on Dean and Crowley. Dar insists she doesn't know where Dean and Crowley are and refuses to call Crowley, stating that he won't answer and the demons are under orders not to call. Dar tells Sam that nobody knows where Dean and Crowley are and to kill her if he wants but she doesn't know anymore. Dar taunts Sam about tricking Lester into selling his soul for nothing and Sam presumably kills her when he gets no more information from her.
Five weeks after starting his trip with Dean, Crowley decides that he needs to feed the Mark of Cain's bloodlust and texts Dean's location in Amherst Junction, Wisconsin to the demon possessing Drew Neely, a demon who is an Abaddon loyalist and wants revenge on Dean for Abaddon's death. Drew finds Dean at a gas station where he's reading porn and draws an angel blade to kill Dean. The two briefly fight, but as a Knight of Hell Dean is much stronger than Drew and easily kills him with the First Blade.
Six weeks after Dean's disappearance and a week after Drew Neely's death, Sam continues to search for signs of demons, reaching out to other hunters for help but coming up with nothing. Sam finally locates an article on Drew's death and suspects that Drew, who was part of a religious order in Northern Ohio before slaughtering his family and disappearing three years before, was possessed by a demon. Seeing Drew's death as a possible lead, Sam contacts Castiel about it, but pretends it was nothing when he realizes that Castiel's condition is worse and he's not doing well. Sam convinces Castiel to stay behind to recuperate and while the two wonder why Dean would take off as he did, they agree that if there's any chance that Dean is still Dean, they need to save him.
In Beulah, North Dakota, Crowley and Dean enjoy letting loose, playing foosball, drinking, doing bad karaoke and Dean sleeping with a waitress named Ann Marie at the Black Spur bar. Ann Marie's ex Matt arrives and gets rough with her which Dean uses as a chance to beat Matt badly under the guise of protecting Ann Marie's honor. As Dean beats Matt, he is watched discreetly by an Abaddon loyalist who Crowley had sent Dean's location as he did with Drew to feed the Mark's bloodlust.
That night, Dean emerges from the bar, having detected the demon watching him and calls him out. The demon emerges and draws an angel blade, telling Dean that he and the surviving Abaddon loyalists can't accept that Abaddon was killed by "a douche" like Dean. Dean draws the First Blade and engages the demon in a brief fight. The demon proves to be no match for the much stronger Dean who easily disarms him and kills the demon with the First Blade.
After finding the article on Drew's death, Sam visits the detective covering the case who tells him that they believe that Drew's death is actually self-defense and shows him the footage of Dean and Drew fighting and Dean killing Drew. As the detective goes to send the picture of Dean from the security footage out, Sam reviews the recording and discovers a shot showing Dean's black eyes. Sam comes to believe that Crowley has had Dean's dead body possessed by a demon and is enraged.
After Dean's picture from the security footage goes out, Cole Trenton is faxed it by a friend of his with the message "yup" attached. Still wanting revenge for what he believes to be his father's murder, Cole packs a bag of weapons and sets out to hunt Dean down and kill him.
Sam visits the Gas 'N Sip Dean killed Drew Neely at in hopes of finding a clue pointing towards his location. While the clerk, Mickey, was too scared to ask Dean any questions, he found Drew's phone following his death and gives it to Sam. Sam finds Crowley's text to Drew and calls him back using Drew's phone while secretly tracing the call using his own phone. Crowley is surprised at first as he believes Drew is calling him, but recovers quickly when he discovers its Sam. Sam confronts Crowley about his belief that Crowley has some demon possessing Dean, but Crowley explains to him that the demon is in fact Dean, Dean having been resurrected by the Mark of Cain as a demon. Sam promises to find a way to save Dean or die trying, but Crowley is just amused, believing that Sam is more upset by the fact that Dean is now friends with Crowley and having the time of his life than he is by Dean being a demon. Enraged, Sam tells him he's going to find Dean, save him and kill Crowley, but Crowley just wishes him luck in finding them and hangs up. After the call ends, Sam checks his phone and discovers that the call lasted long enough to trace it to the Black Spur in Beulah, North Dakota.
Crowley explains to Dean about how he sent the demons after him to sate the Mark's bloodlust and keep him Dean sharp. Crowley has had enough and wants to stop "howling at the moon" and return to ruling Hell with Dean at his side, believing that together they could create the perfect Hell. However, Dean is uninterested in the idea and wants to keep enjoying himself without constraint. Crowley then reveals that Sam called and he purposefully let Sam trace the call in order to force Dean to make a choice. Crowley tells Dean to take the night to make up his mind before departing.
Having gotten Dean's location, Sam makes his way towards the Black Spur followed, unknown to him, by Cole. Cole eventually uses a kill switch he installed to disable Sam's car and approaches him under the pretense of offering Sam his help. After pointing the kill switch out to Sam, Cole knocks him out and kidnaps Sam.
At the Black Spur, Dean continues to indulge himself heavily and asks Ann Marie to leave with him, claiming that he defended her honor when she points out that she barely knows him. However, Ann Marie recognizes that the fight has nothing to do with defending her honor at all and Dean tells her that he's just the kind of guy that sleeps with every skank in every small-town dive he passes through, upsetting Ann Marie which Dean doesn't care about. Dean then finally departs the Black Spur before Sam can catch up, leaving his tab at the bar open for Sam.
Cole takes Sam to a barn and ties him up before introducing himself and revealing that he knows who Sam is. After Cole tells him that he and Dean "go way back", Sam asks if Cole is a hunter which he decides to go with as he's hunting down Dean, not understanding that Sam means a monster hunter. Sam tries to dissuade Cole from hunting Dean, telling him that Dean is a monster and Cole should go back to his life, but Cole just tells him that Dean was a monster a long time ago but now he's prey and Cole's the monster.
Using Sam's phone, Cole calls Dean who is driving the Impala and decides to answer. Cole tells Dean that he's karma and as long as Dean shows up where Cole tells him to when Cole tells him to, Sam will live. After Dean demands proof that Sam is alive, Cole punches Sam to make him cry out after Sam refuses to speak. Dean, no longer caring about Sam as a demon, tells Cole that he won't be meeting up with him or trading himself for Sam and that all Cole is getting from his is a promise that somewhere down the road, Dean will find and kill him. Though Cole threatens to kill Sam, Dean is unrepentant, telling Cole that Sam should've let him go as Dean told him to in his message and whatever jam Sam is in now, is his own problem. Though Cole continues to threaten Sam, Dean tells Cole that he's a man of his word and hangs up, not caring about the danger Sam is in at all.
After his phone call with Dean, Cole explains to Sam how he believes that Dean murdered his father when he was a kid and that he intends to get revenge. Though Sam offers his sympathy, Cole is uninterested and asks for Dean's location, pointing out that Dean just gave him permission to kill Sam. Sam refuses and tries to convince Cole about the existence of monsters. Though Cole knows about human monsters from his time in Special Ops, he refuses to believe Sam about monsters such as vampires and werewolves even after Sam points him to a flask of holy water in his bag.
Since Sam refuses to cooperate, Cole decides to resort to torture to get what he wants from him. Cole begins beating Sam, trying to get an answer out of him then grips his injured shoulder tightly. Sam still refuses to break, so Cole threatens to break his knees. Before he can do it, he gets a call from his family and leaves to talk to them. As he pulls out his phone, he drops his key ring on which there is a pocket knife, allowing Sam to cut himself free and escape. He then calls Castiel to get to Beulah, North Dakota to meet up with him and help catch Dean. Sam informs Castiel that Dean is now a demon due to the Mark and even though he knows Castiel isn't doing so well, he needs all the help he can get. Castiel agrees to meet Sam and help him while Sam steals a truck to reach Dean.
Having moved on to Killdeer, North Dakota, Dean visits a strip club where he gets too handsy with a stripper. When a security guard tries to intervene, Dean beats him badly before taking his money and leaving. Outside, Crowley appears and tells Dean they need to talk about his "anger management issues."
At a bar, Crowley points out how on edge Dean is due to the Mark's bloodlust and tells him that he needs to sate it once more in order not to lose control of himself. Crowley suggests that Dean fulfill Lester Morris' deal by killing his wife Mindy for Crowley, stating that she will die either way so Dean should do it. Dean agrees to do this one job for Crowley who tells him about Sam's involvement in Lester's deal before Dean leaves.
Outside of Lester's house, as Dean prepares to enter and kill Mindy, he is surprised when Lester pulls in. Dean climbs into Lester's car and Lester explains that he had heard that the hit was going down that night and wanted to see it done right. Lester claims that Mindy ruined his life while Dean just feels that Lester is a loser and that Mindy can't be blamed for stepping out on him, particularly if Lester had cheated on his wife first. Lester at first denies it, but eventually admits that he did cheat but sees it as different when guys do it, calling it science and claiming that men aren't built for monogamy. Angry, Dean punches Lester and calls him a loser causing Lester to call him a "punk-ass demon" and to tell Dean that Dean works him for him now and he needs to get in the house and kill Mindy. Enraged by Lester's words, Dean asks if he would enjoy watching Dean kill Mindy before killing Lester instead with the First Blade.
Sam learns of the security guard getting beaten up at the strip club and visits the man who confirms that Dean is the one who attacked him. The security guard agrees to call Sam if he sees Dean again and Sam leaves, unaware that Cole is following him in an effort to find Dean for himself.
As Crowley gets a report that Sam is close by, Dean returns to the bar and reveals to Crowley that he killed Lester instead of Mindy, enraging Crowley as by killing Lester instead of fulfilling his deal, Crowley can't claim Lester's soul. Dean is unrepentant and when Crowley yells at him, shoves him to the floor. Crowley tells Dean he doesn't think Dean knows what he wants and he needs to pick a side. Unthreatened, Dean challenges Crowley to attack him and states that he isn't Crowley's "bestie" and he doesn't take orders from him and will only call Crowley when he needs someone to kill. Until then, Dean demands that Crowley stay out of his way. Crowley agrees, telling Dean that their relationship is over and leaves.
Finding Dean to be bad for business, Crowley visits Sam outside of a hotel and tells Sam he's there to give Dean back to him to deal with due to Dean being so uncontrollable. In return, Crowley asks for possession of the First Blade to keep it out of Dean's hands. Sam agrees to the deal and Crowley points Sam at the bar where Dean is still located.
Sam goes to the bar where he finally meets Dean face to face for the first time since Dean became a demon. Dean reminds Sam he'd told Sam to let him go, but Sam admits that he couldn't do it and that Crowley sold Dean out. As Dean heads across the room with the First Blade, Sam tells Dean that he doesn't have to be a demon as they know how to cure demons. Dean remembers, but tells Sam that if he'd wanted to be cured, he wouldn't have bailed on Sam and would've stayed. While Sam suggests that it was Crowley's influence, Dean tells him that it really wasn't and responds to Sam's promise that whatever happened they will fix it by telling him that its all Dean can do not to rip Sam's throat out with his teeth. Dean gives Sam a chance to walk away, but Sam refuses and Dean refuses to go with him, asking if Sam will kill him now. Sam refuses even when Dean suggests he might have it coming and Sam tells him that its because Dean is his brother and he's there to take him home. Dean mocks Sam's words and Sam draws the Supernatural Handcuffs to use on Dean even though Dean suggests they might not work on him.
Before things can escalate further, Cole attacks with a tear gas grenade through the window, driving Sam outside where Cole knocks him out and reveals to Dean that he allowed Sam to escape so he could follow him to Dean. Cole confronts Dean about his father's death, but Dean could care less, telling Cole that he's killed a lot of people a lot of people and he can't remember Edward Trenton specifically because of it. Cole, who had drawn a gun on Dean, puts it away and draws a knife instead to kill him in hand-to-hand combat. Cole proves no match for Dean who easily counters all of Cole's moves and disarms him of both his gun and knife, mocking him all the while. Eventually, Cole manages to cut Dean's face open with a second knife, but it quickly heals right in front of a shocked Cole. Dean explains that he's a demon to Cole, showing Cole his black eyes before Dean beats him into submission. Dean draws the First Blade and holds it to Cole's throat, but ultimately doesn't kill him, telling Cole that he changed his mind.
While Dean is distracted fighting Cole, Sam recovers and returns to the bar to retrieve the Supernatural Handcuffs. After Cole is defeated, Sam splashes Dean with holy water, distracting Dean long enough for Sam to handcuff and capture him. Afterwards, Sam turns the First Blade over to Crowley who promises to store it somewhere far away from Dean as he doesn't want Dean getting his hands on it anymore than Sam does. Still wanting revenge, Cole begins researching into demons while Dean tells Sam that he didn't show Cole mercy because Cole spent his whole life plotting revenge on him for killing his father's death and will now have to live with knowing he had his shot and couldn't take it. Dean explains that letting Cole live was the worst thing he could've done to him and promises that what he will do to Sam won't be mercy either.
Sam takes Dean to the Men of Letters bunker and locks him in the dungeon before preparing for the ritual to cure Dean of being a demon. To this end, Sam travels to a nearby hospital where he disguises himself as a doctor and has a priest perform a blood blessing over a container of blood, turning it into purified blood that can be used in the ritual.
Sam returns to the bunker and consecrates the dungeon floor while Dean tells Sam that he knows Sam thinks he's going to try and fix Dean, but Dean doesn't want to be fixed. Dean tells Sam that he won't be like Crowley when Sam performed the ritual on him and won't "get all weepy" and continues to insist he doesn't want to be cured. Dean reminds Sam that he also has the Mark of Cain running through his veins and not just "demon juice", but Sam refuses to stop. As Dean roars at him, Sam splashes him with holy water and then injects the first dose of blood, telling Dean he can make it easier on himself by cooperating. The injection Sam gives him causes Dean a lot of pain immediately following Sam giving it to him.
Awhile later, Sam gives Dean his next injection, causing him more pain. Dean tells Sam that Sam could be killing him for all he knows, but Sam states that the lore says nothing about exceptions to the cure. Dean tells Sam that he finds the lore and hunting all "a load of crap" and that he's the "new real me" who sees things the way they are: while the Winchesters and other "do-gooders" fight the natural order of things, guys like him are the natural order and its the way things were set up. Sam responds by stating that guys like him have to do what they can, but Dean feels that there's not much difference between what he turned into and what Sam already is. When Sam questions the statement, Dean reminds him of Sam tricking Lester Morris into selling his soul to capture Dar, having learned about it from Crowley. Dean taunts Sam that he killed Lester himself and his wife married that guy she had cheated with. Dean is amused by the fact that Sam might be worse than him since Sam took a guy at his worst, used him and in doing so cost him his life and his soul. Enraged, Sam gives Dean the next injection in the back of his neck and Dean reminds Sam that if the cure doesn't work, Sam will have to kill him. Dean asks Sam if he can do that if it comes down to it, a question for which Sam has no answer.
Worried about the pain that Dean is in, Sam calls Castiel. Castiel, who's grace has faded to nearly nothing and is getting weaker, tells Sam that he's still a few hours away from the bunker and Sam tells him about how the effects of the ritual are causing Dean a lot of pain and Sam could be killing him with it. Castiel admits that it might be the case but Sam has no other choice since Dean is not possessed so an exorcism wouldn't work on him. Castiel also knows of no other cure than the one Sam is trying and if it fails, Sam will have to kill Dean. Sam reluctantly acknowledges this and hangs up after Castiel promises to be there as soon as he can.
Returning to the dungeon, Sam finds that the pain Dean is going through has caused him to pass out. Sam wakes Dean who describes what he's going through as "drowning in your own sweat while your blood boils", but Sam refuses to give up on bringing human Dean back. Dean tells Sam that his brother has been gone for a long time and he is now "lean, mean, Dean" which he is loving. Dean reminds Sam that the first thing he did after becoming a demon was to get as far away from Sam as possible, choosing the King of Hell over him and suggests that its because he's tired of saving Sam all the time. Dean also suggests that its because without Sam, his mother would still be alive and Sam's life has sucked the life out of Dean's life. Dean announces that he quits the family, but Sam refuses to let him quit as their family is all they've got. Dean feels that they've got nothing then and speaks badly of their father when Sam wonders what he would think of Dean's sentiments. Having had enough of Dean's comments, Sam injects him with the next dose of purified blood, stating "this is me, yanking your lame ass out of the fire." Sam then leaves the room as Dean gasps in pain from the effects of the purified blood on him.
After spending some time looking at old pictures, Sam returns to the dungeon to find Dean gone. Sam draws the demon-killing knife and sneaks through the bunker as Dean searches for him, taking a hammer to use as a weapon from the kitchen. Sam makes his way into the bunker's electrical room and activates the bunker's lockdown mode to keep Dean from escaping. Dean admits that he's impressed by the move, but has no intention of leaving the bunker until he finds Sam. As he searches, Dean explains that the cure made him human enough that the Supernatural Handcuffs no longer worked on him and while it smarted, he was able to leave the devil's trap in the dungeon. Dean enters the electrical room and shuts down the lockdown, but Sam takes the opportunity to lock him in the room. Sam pleads with Dean to let him finish the cure since they were getting close, but Dean starts breaking down the door with his hammer, telling Sam that he has no desire to be cured and he likes the "disease" of being a demon. Sam tries to threaten Dean into stopping, but Dean recognizes that Sam won't be able to bring himself to kill him while Dean has enough demon left in him that killing Sam won't be a problem for him. As Dean escapes the room, Sam flees down the hall but is found by Dean who swings his hammer at Sam's head. Dean misses when Sam ducks, getting his hammer stuck in the wall and Sam gets the drop on him, holding the demon-killing knife to his throat. Dean challenges Sam to kill him, but Sam lowers the knife instead. Dean starts to advance on Sam, believing he's won, but is restrained from behind by Castiel who's grace had been replenished with Crowley's help.
Castiel and Sam return Dean to his restraints and complete the remaining injections of purified blood. After giving Dean the last dose, Sam wonders if they are doing the right thing since even after he had been given so many doses, Dean still had no desire to return to humanity. Castiel admits that he can see Dean's point as only humans can feel real joy but also profound pain and being non-human is easier. Dean regains consciousness and his black eyes melt away as he regains his humanity. With Castiel prepared with his angel blade in case the cure didn't work, Sam splashes Dean with holy water to no effect, confirming that Dean has been cured and is now human once again.
After Dean is successfully cured, Sam and Castiel acknowledge that while they have solved the problem of Dean being a demon, he still has the Mark of Cain which will eventually become a problem again that has to be dealt with. Sam sees it as a problem for another day while Dean is left horrified by the acts he committed as a demon. Castiel suggests that since things are relatively quiet now, that the Winchesters take some time off of hunting to recuperate for a while. While Sam and Dean follow Castiel's advice and take a break, they return to hunting after learning of a werewolf case.
Following his encounter with the demonic Dean, Cole chooses to continue his quest for revenge and does research into demons, learning about holy water and devil's traps at the very least. Months later, Cole tracks down Dean again as he and Sam go after Rowena and faces off with Dean again. Dean defeats Cole in a fight but is able to convince him of the truth about his father's death, causing Cole to give up his revenge and go back to his family. After being possessed by a Khan Worm, Cole comes to understand why Dean killed his father and forgives him for it.
- While fighting Cole, Dean makes a reference to the movie The Princess Bride. Crowley also makes a reference to the Lord of the Rings when he calls the First Blade "the Precious."
- The ritual Sam uses to cure Dean is slightly different than the ritual depicted in Clip Show and Sacrifice that Sam attempted to use to cure Crowley.
- In Paper Moon, Sam admits to Dean that while Lester Morris was the only innocent man he involved in his hunt for Dean, he rubbed "or punched" a few hunters the wrong way during the hunt.